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Method and compositions for treating pulmonary diseasesRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Cyclopentanohydrophenanthrene Ring System Doai, With Additional Active IngredientMethod and compositions for treating pulmonary diseases description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20060035877, Method and compositions for treating pulmonary diseases. Brief Patent Description - Full Patent Description - Patent Application Claims
AREA OF THE INVENTION [0001] This invention relates compositions and methods for preventing or reducing the onset of symptoms of pulmonary diseases, or treating or reducing the severity of pulmonary diseases. In particular it relates to compositions and methods for treating pulmonary diseases mediated by phosphodiesterase 4 (PDE4) by administering a PDE4 inhibitor with an anti-inflammatory corticosteroid. BACKGROUND OF THE INVENTION [0002] Identification of novel therapeutic agents for treating pulmonary diseases is made difficult by the fact that multiple mediators are responsible for the development of the disease. Thus, it seems unlikely that eliminating the effects of a single mediator could have a substantial effect on all three components of chronic asthma. An alternative to the "mediator approach" is to regulate the activity of the cells responsible for the pathophysiology of the disease. [0003] One such way is by elevating levels of cAMP (adenosine cyclic 3',5'-monophosphate). Cyclic AMP has been shown to be a second messenger mediating the biologic responses to a wide range of hormones, neurotransmitters and drugs; [Krebs Endocrinology Proceedings of the 4th International Congress Excerpta Medica, 17-29, 1973]. When the appropriate agonist binds to specific cell surface receptors, adenylate cyclase is activated, which converts Mg.sup.+2-ATP to cAMP at an accelerated rate. Cyclic AMP modulates the activity of most, if not all, of the cells that contribute to the pathophysiology of extrinsic (allergic) asthma. As such, an elevation of cAMP would produce beneficial effects including: 1) airway smooth muscle relaxation, 2) inhibition of mast cell mediator release, 3) suppression of neutrophil degranulation, 4) inhibition of basophil degranulation, and 5) inhibition of monocyte and macrophage activation. Hence, compounds that activate adenylate cyclase or inhibit phosphodiesterase should be effective in suppressing the inappropriate activation of airway smooth muscle and a wide variety of inflammatory cells. The principal cellular mechanism for the inactivation of cAMP is hydrolysis of the 3'-phosphodiester bond by one or more of a family of isozymes referred to as cyclic nucleotide phosphodiesterases (PDEs). [0004] It has been shown that a distinct cyclic nucleotide phosphodiesterase (PDE) isozyme, PDE4, is responsible for cAMP breakdown in airway smooth muscle and inflammatory cells. [Torphy, "Phosphodiesterase Isozymes: Potential Targets for Novel Anti-asthmatic Agents" in New Drugs for Asthma, Barnes, ed. IBC Technical Services Ltd., 1989]. Research indicates that inhibition of this enzyme not only produces airway smooth muscle relaxation, but also suppresses degranulation of mast cells, basophils and neutrophils along with inhibiting the activation of monocytes and neutrophils. Moreover, the beneficial effects of PDE 4 inhibitors are markedly potentiated when adenylate cyclase activity of target cells is elevated by appropriate hormones or autocoids, as would be the case in vivo. Thus PDE 4 inhibitors would be effective in the lung, where levels of prostaglandin E.sub.2 and prostacyclin (activators of adenylate cyclase) are elevated. Such compounds would offer a unique approach toward the pharmacotherapy of bronchial asthma and possess significant therapeutic advantages over agents currently on the market. [0005] In addition, it could be useful to combine therapies in light of the fact that the etiology of many pulmonary diseases involves multiple mediators. In this invention there is presented the combination of a PDE 4 inhibitor and an anti-inflammatory corticosteroid, particularly one delivered by inhalation, for treating pulmonary diseases. This combination is particularly useful for treating chronic obstructive pulmonary disease (COPD) or asthma. SUMMARY OF THE INVENTION [0006] In a first aspect this invention relates to a method for treating a pulmonary disease in a mammal by administering to a patient in need thereof an effective amount of a PDE 4-specific inhibitor and an effective amount of a steroidal anti-inflammatory agent wherein the drugs are administered concomitantly together or separately and sequentially where the sequential administration is close in time or remote in time. [0007] In a second aspect this invention relates to a composition for treating a pulmonary disease in a mammal comprising an effective amount of a PDE4-specific inhibitor, an effective amount of a steroidal anti-inflammatory agent and a pharmaceutically acceptable excipient. DETAILED DESCRIPTION OF THE INVENTION [0008] The combination therapy contemplated by this invention comprises administering a PDE4 inhibitor with a steroidal anti-inflammatory agent to prevent onset of a pulmonary disease event or to treat an existing condition. The compounds may be administered together in a single dosage form. Or they may be administered as two different formulations which may be the same or different. To illustrate, both drugs may be provided separately as oral formulations, or one may be an oral preparation and the other as an inhalant, or both may be provided in an inhaled dose form. They may be administered at the same time. Or they may be administered either close in time or remotely, such as where one drug is administered in the morning and the second drug is administered in the evening. [0009] The combination may be used prophylactically or after the onset of symptoms. In some instances the combination(s) may be used to prevent the progression of a pulmonary disease or to arrest the decline of a function, such as lung function. [0010] The PDE4-specific inhibitor useful in this invention may be any compound that is known to inhibit the PDE4 enzyme or which is discovered to act in as PDE4 inhibitor, and which are only PDE4 inhibitors, not compounds which inhibit other members of the PDE family as well as PDE4. Generally it is preferred to use a PDE4 antagonists which has an IC.sub.50 ratio of about 0.1 or greater as regards the IC.sub.50 for the PDE4 catalytic form which binds rolipram with a high affinity divided by the IC.sub.50 for the form which binds rolipram with a low affinity. [0011] PDE inhibitors used in treating inflammation and as bronchodilators, drugs like theophylline and pentoxyfyllin, inhibit PDE isozymes indiscriminately in all tissues. These compounds exhibit side effects, apparently because they non-selectively inhibit all 5 PDE isozyme classes in all tissues. The targeted disease state may be effectively treated by such compounds, but unwanted secondary effects may be exhibited which, if they could be avoided or minimized, would increase the overall therapeutic effect of this approach to treating certain disease states. For example, clinical studies with the selective PDE 4 inhibitor rolipram, which was being developed as an antidepressant, indicate it has psychotropic activity and produces gastrointestinal effects, e.g., pyrosis, nausea and emesis. [0012] For purposes of this disclosure, the cAMP catalytic site which binds R and S rolipram with a low affinity is denominated the "low affinity" binding site (LPDE 4) and the other form of this catalytic site which binds rolipram with a high affinity is denominated the "high affinity" binding site (HPDE 4). This term "HPDE4" should not be confused with the term "hPDE4" which is used to denote human PDE4. [0013] Initial experiments were conducted to establish and validate a [3H]-rolipram binding assay. Details of this work are given in Example 1 below. [0014] To determine whether both the high affinity binding activity and the low affinity binding activity resided in the same gene product, yeast-were transformed by known methods and the expression of recombinant PDE 4 was followed over a 6 hour fermentation period. Western blot analysis using an antibody directed against PDE 4 indicated that the amount of PDE 4 expressed increased with time, reaching a maximum after 3 hour of growth. In addition, greater than 90% of the immunoreactive product was in the high speed (100,000.times.g) supernatant of yeast lysates. [.sup.3H]R-(-)-Rolipram binding and PDE activity were monitored along with protein expression. PDE 4 activity was co-expressed with rolipram binding activity, indicating that both functions exist on the same gene product. Similar to results with the Western plot analysis, greater than 85% of the rolipram-inhibitable PDE activity and [.sup.3H]-rolipram binding activity was found to be present in the yeast supernatant fraction. [0015] Overall, most of the recombinant PDE 4 expressed in this system exists as LPDE 4 and only a small fraction as HPDE 4. Consequently, inhibition of recombinant PDE 4 catalytic activity primarily reflects the actions of compounds at LPDE 4. Inhibition of PDE 4 catalytic activity can thus be used as an index of the potency of compounds at LPDE 4. The potency of compounds at HPDE 4 can be assessed by examining their ability to compete for [.sup.3H]R-rolipram. To develop SARs for both the low affinity and high affinity rolipram binding sites, the potencies of selected compounds were determined in two assay systems. Results from experiments using standard compounds were tabulated. As expected, certain compounds were clearly more potent in competing with [.sup.3H]-rolipram at the site for which rolipram demonstrated high affinity binding as compared with the other site, the one at which rolipram is a low affinity binder. SAR correlation between high affinity binding and low affinity binding was poor and it was concluded that the SAR for inhibition of high affinity [.sup.3H]-rolipram binding was distinct from the SAR for binding to the low affinity rolipram binding site. [0016] It is now known that there are at least two binding forms on human monocyte recombinant PDE 4 (hPDE 4) with which inhibitors interact. One explanation for these observations is that hPDE 4 exists in two distinct forms. One binds the likes of rolipram and denbufylline with a high affinity while the other binds these compounds with a low affinity. The preferred PDE4 inhibitors of use in this invention will be those compounds which have a salutary therapeutic ratio, i.e., compounds which preferentially inhibit cAMP catalytic activity where the enzyme is in the form that binds rolipram with a low affinity, thereby reducing the side effects which apparently are linked to inhibiting the form which binds rolipram with a high affinity. Another way to state this is that the preferred compounds will have an IC.sub.50 ratio of about 0.1 or greater as regards the IC.sub.50 for the PDE 4 catalytic form which binds rolipram with a high affinity divided by the IC.sub.50 for the form which binds rolipram with a low affinity. [0017] A further refinement of this standard is that of one wherein the PDE4 inhibitor has an IC.sub.50 ratio of about 0.1 or greater; said ratio is the ratio of the IC.sub.50 value for competing with the binding of 1 nM of [.sup.3H]R-rolipram to a form of PDE 4 which binds rolipram with a high affinity over the IC.sub.50 value for inhibiting the PDE4 catalytic activity of a form which binds rolipram with a low affinity using 1 microM[.sup.3H]-cAMP as the substrate. A further review explanation with of this test can be found in co-pending U.S. application Ser. No. 08/456,274 filed 31 May 1995, the text of which is incorporated herein by reference to the extent that text is necessary to the practice of this invention. [0018] Examples of useful PDE4 inhibitors are: [0019] (R)-(+)-1-4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrroli- done; [0020] (R)-(+)-1-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphe- nyl]-2-pyrrolidone, [0021] 3-(cyclopentyloxy-4-methoxyphenyl)-1-4-N'-[N2-- cyano-S-methyl-isothioureido]benzyl)-2-pyrrolidone, [0022] cis 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-carboxylic acid]; [0023] cis-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphen- yl)cyclohexan-1-ol]; [0024] (R)-(+)-ethyl [4-(3-cyclopentyloxy-4-methoxyp- henyl)pyrrolidine-2-ylidene)acetate; [0025] (S)(-)-ethyl [4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidine-2-ylidene]acetate, [0026] Most preferred are those PDE 4 inhibitors which have an IC.sub.50 ratio of greater than 0.5, and particularly those compounds having a ratio of greater than 1.0. Preferred compounds are cis 4-cyano-4-(3-cyclopentyloxymethoxyphenyl)cyclohexan-1-carboxylic acid, 2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cy- clohexan-1-one, and is-[4-cyano-4-(3-cyclopropylmethoxyX difluoromethoxyphenyl)cyclohexan-1-ol]; these are examples of compounds which bind preferentially to the low affinity binding site and which have an IC.sub.50 ratio of 0.1 or greater. [0027] Compounds set out in U.S. Pat. No. 5,552,438 issued 03 Sep., 1996. This patent and the compounds it discloses are incorporated herein in full by reference. The compound of particular interest, which is disclosed in U.S. Pat. No. 5,552,438, is cis-4-cyano-4-[3-(cyclopentyloxy- ).sub.4-methoxyphenyl]cyclohexane-1-carboxylic acid and its salts, esters, pro-drugs or physical forms. Continue reading about Method and compositions for treating pulmonary diseases... 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